Scientists Present Grand Unified Theory of C-Myc

The transcription factor c-Myc is an oncoprotein; that much has long been clear. The c-myc gene is a known or suspected driver mutation in many cancer types.

In fact, one of the major goals is making induced pluripotent stem (iPS) cells, where it is one of the four "magic factors" that can transform fibroblasts back into a stem-cell-like state.

But as for how Myc does what it does has been the subject of contradictory findings and heated debate. For example, Myc "appeared to have different targets in different cells," David Levens, of the National Cancer Institute's Center for Cancer Research, told BioWorld Today. And small differences in Myc levels could make for big differences in results: The protein "seems to have different thresholds for different phenomena."

Now, two groups have offered a simple explanation for how Myc works that could reconcile many of what Levens termed the "disparate and even contradictory findings" that have been published about Myc over the years.

Their results, which were published in back-to-back papers in the Sept. 28, 2012, issue of Cell, indicated that rather than having certain target pathways, Myc, when it is turned on, will amplify the expression of whatever genes are already active in a cell.

The two papers used different methods. One, by researchers from the Whitehead Institute, transfected cancer cell lines with Myc to gauge its effects. Researchers from the National Institutes of Health, on the other hand, "used a mouse strain with green fluorescent protein knocked into the c-Myc locus," co-corresponding author Keji Zhao told BioWorld Today. Zhao is at the National Heart Lung and Blood Institute.

Both papers, though, came to converging conclusions about the big picture. Rather than activating any particular pathways, Myc, when it is expressed, will gravitate to DNA that is already being actively transcribed, and bump up that active transcription still further. And highly expressed genes are the ones that are most strongly amplified.

Under normal circumstances, Myc is produced in a pulse in response to stress. For an effective stress response, co-corresponding author Levens said, that strategy makes sense, because "it allows cells to adapt to a new situation more quickly." In such a new situation, he added, most often, "to a first approximation, what a cell needs is more of what it already has" – which is what a general increase in transcription delivers.

He likened the cellular response to stress to Pearl Harbor. "What the country needed was more of what was already being produced: more weapons, more ammunition, more of everything. And quickly, before there was time to do an exquisite accounting."

In his opinion, that also is what Myc is doing as part of the cocktail that induces a pluripotent state in iPS cells. "I don't think it is really helping select what genes to activate," he said. Instead, "it helps lock cells into this new state" that is initiated by the other transforming factors.

Myc is usually active only in brief spurts. Longer-term activity turns cells into tumor cells. The findings now published in Cell suggested that the reason is not that increased levels of Myc activate fundamentally different pathways. Rather, Myc is activating the same paths in sickness and in health – but their constant activation sends cells into a proliferative frenzy.

As for what the findings imply for targeting Myc for the treatment of cancer, Levens said the message is overall "hopeful."

The fact that Myc acts as an amplifier rather than activating a specific target does mean the protein itself, or its binding sites on the DNA, would have to be targeted, and targeting transcription factors has proven to be tricky due to their biophysical properties. But the nonlinear nature of the cellular response to Myc, he said, also means that "Myc does not have to be [silenced] completely. I believe that in all likelihood, small changes in Myc expression will lead to dramatic changes in cell physiology. . . . I don't think you'll need a 90 percent knockdown of Myc" to affect tumor cells.